Abundant evidence from animal and human studies suggests that the calcineurin pathway is a key mediator in the pathogenesis of left ventricular hypertrophy (LVH). Previous studies suggest that variation in genes involved in this pathway contributes to the risk of LVH. However, causal variants have not been identified. In addition, almost all human studies of in-situ activation of the calcineurin pathway in relation to LVH were based on transplant hearts and there are no reports of population-based studies to evaluate whether serum calcineurin protein level and enzymatic activity can serve as biomarkers of activated calcineurin pathways in the human heart. The objective of the proposed study is to evaluate the utility of serum calcineurin protein and enzymatic activity as biomarkers for LVH at the population level and to identify variants in genes involved in the calcineurin pathway that contribute to the risk of LVH. Utilizing genotype data and specimens collected from the Hypertension Genetic Epidemiology Network - Genetics of Left Ventricular Hypertrophy Study (HyperGEN- LVH) of the Family Blood Pressure Program (FBPP), we propose four aims 1) to develop assays to measure serum calcineurin protein level and enzymatic activity, apply the assays to serum samples of 1101 hypertensive African Americans, and test associations between protein level and enzymatic activity with LVH;2) to conduct a genetic association study of 140 SNPs in four candidate genes (CnA1, CnA2, CnB1, and MCIP1) involved in the calcineurin pathway with serum calcineurin protein level and enzymatic activity;3) to evaluate associations of LVH with the 140 SNPs plus another 9 SNPs of NFATC4, which is a downstream target of calcineurin and participates in regulating LVH, and 4) to replicate significant genetic findings in the African-American participants from the FBPP-GENOA network who were phenotyped for LVH using the HyperGEN protocol and reading center. We anticipate that results from this study will provide greater understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for screening tests and novel pharmacological targets to prevent or treat LVH in hypertensive subjects. PUBLIC HEALTH RELEVANCE: The proposed study could lead to a breakthrough in the understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for epidemiological studies of the calcineurin pathway in LVH. This project could also have a major impact on the design of clinical trials to pharmacologically target the calcineurin pathway to prevent and treat LVH in hypertensive subjects.